Postoperative cognitive dysfunction (POCD) is a well-documented disease affecting patients after cardiac and non-cardiac surgeries. Age is a significant risk factor for middle- term POCD. About 10% elderly patients (? 60 years old) have POCD 3 months after non- cardiac surgery. POCD not only affects patients? daily activity but also predicts high mortality. Currently, effective and clinically practical methods to reduce POCD are not established. Our recent study showed that environmental enrichment (EE) reduced post- surgery learning and memory impairment in young adult male mice. EE also attenuated surgery-induced reduction of sex determining region Y-box-2 (Sox2), a transcription factor that is critical for maintaining pluripotency of stem cells. Silencing Sox2 impaired learning and memory. In addition, surgery also reduced sirtuin 1 (SIRT1), a deacetylase that can directly induce Sox2 expression. In this project, we will define the characteristics of EE that can attenuate learning and memory impairment in elderly mice. The hypothesis that EE attenuates surgery-induced learning and memory impairment via SRT1-Sox2 pathway after surgery will also be tested. Twenty-month old mice will be subjected to a surgical procedure often performed in elderly patients. Some mice will be exposed to EE that includes toys, running wheel and tunnels in the cage for 14 days. Their learning and memory will then be tested. SIRT1 inhibitor, activator and silencing will be used. These studies will provide pre- clinical evidence for potentially using EE to reduce POCD. They will also identify mechanisms for this effect. In addition, our study may provide initial evidence for stem cells to be involved in learning and memory.